Galectin-1 (Gal1), a member of a conserved family of carbohydrate-binding proteins, modulates immune responses and fosters tumor-immune escape through specific recognition of N-acetyllactosamine (Gal-β1-4-NAcGlc) residues on the branches of N- or O-linked glycans (Juszczynski et al. (2007) Proc Natl Acad Sci USA. 104:13134-13139; Rabinovich and Croci (2012) Immunity 36:322-335; Rabinovich and Toscano (2009) Nat. Rev Immunol, 9:338-352; Rubinstein et al. (2004) Cancer Cell 5:241-251).
Gal1 selectively induces the apoptosis of cytotoxic T cells and T helper (Th) 1 and Th17 cells by interacting with specifically sialated cell surface glycoproteins, such as CD45, CD43 and CD7 (Toscano et al. (2007) Nat. Immunol. 8:825-834). Since Th2 cells and regulatory T (Treg) cells lack the Gal1-binding glycoprotein motif, Gal1 spares these cells and fosters an immunosuppressive Th2/Treg-enriched tumor microenvironment (Toscano et al. (2007) Nat. Immunol. 8:825-834). Gal1 also promotes the expansion of regulatory T (Treg) cells (Juszczynski et al. (2007) Proc Natl Acad Sci USA. 104:13134-13139; Toscano et al. (2007) Nat. Immunol., 8:825-834) and Gal1-glycan interactions augment hypoxia-driven tumor angiogenesis (Croci et al. (2012). J. Exp. Med. 209; 1985-2000).
These molecular mechanisms underlie the effect of Gal1 on promoting classical Hodgkin lymphoma (cHL). cHL is a B-cell malignancy diagnosed in approximately 20,000 new patients in North America and Europe each year; >90% of these patients are young adults. cHL include small numbers of malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive Th2/Treg-skewed inflammatory infiltrate (Küppers et al. (2002) Ann. Oncol. 13:11-18; Juszczynski et al. (2007) Proc Natl Acad Sci U.S.A. 104:13134-13139; Küppers (2009) Nat. Rev. Cancer 9:15-27). HRS cells overexpress Gal1, which selectively Th1 and cytotoxic T cells and promotes the immunosuppressive Th2/Treg-predominant HL microenvironment (Juszczynski et al. (2007) Proc Natl Acad Sci USA. 104:13134-13139). HRS cells lack B-cell receptor-mediated signals and rely on alternative survival and proliferative pathways activated by transcription factors, such as NF-κB and activator protein 1 (AP1) (Küppes et al. (2002) Ann. Oncol. 13:11-18; Mathas et al. (2002) EMBO J. 21:4104-4113; Schwering et al. (2003) Mol. Med. 9:85-95). In cHL, the tumor cells exhibit constitutive AP1 activation, express high levels of the AP1 components, cJun and Jun B, and depend on AP1-mediated proliferation signals (Mathas et al (2002) EMBO J. 21:4104-4113; Juszczynski al. (2007) Proc Acad Sci USA. 104:13134-13139; Rodig et al. (2008) Clin. Cancer Res. 14:3338-3344). Although primary cHLs have a brisk inflammatory infiltrate, there is little evidence of an effective host antitumor immune response. The reactive T cell population included predominantly Th2-type and CD4+CD25hiFoxP3+ regulatory T cells that directly suppress immune responses and protect HRS cells from immune attack (Re et al. (2005) J. Clin. Oncol. 23:6379-6386; Marshall et al. (2004) Blood 103:1755-1762; Gandhi et al. (2006) Blood 108:2280-2289). Th1 and natural killer and cytotoxic T cells are markedly underrepresented.
Increased Gal1 expression in immunohistochemical analyses of primary cHLs is associated with poorer event-free survival (Kamper et al. (2011) Blood 117:6638-6649). In particular; elevated serum Gal1 levels are significantly associated with tumor burden and adverse clinical features in newly diagnosed patients with cHL (Ouyang et al. (2013) Blood 121:3431-3433). Moreover, Gal1 expression is also associated with EBV-associated post-transplant lymphoproliferative disorder (PTLD) (Gottschalk et al. (2005). Annu. Res. Mol. 56:29-44; Ouyang et al. (2011) Blood 117:4165-4166 and 4315-4322), MLL-rearranged ALL (Juszczynski et al (2010) Clin. Cancer Res. 16:2122-2130), and Kaposi's sarcoma (Tang et al. (2010) Oncol. Rep. 24:495-500). In addition to these select lymphoid malignancies and virally induced cancers, Gal1 is also expressed by many solid tumors, including, breast cancer (Croci al, (2012) J. Exp. Med. 209:1985-2000), prostate cancer (Dalotto-Moreno et al. (2013) Cancer Res. 73:1107-1117), lung cancer (Laderach et al. (2013) Cancer Res. 73:86-96), pancreatic cancer (Chung et al. (2012) Clin. Cancer Res. 18:4037-4047), squamous cell carcinoma of the head and neck (Chung et al. (2008) ANZ J. Surg. 78:245-251; Alves et al. (2011) Pathol. Res. Pract. 207:236-40), hepatocellular carcinoma (Le et al. (2005) J. Clin. Oncol. 23:8932-41), nasopharyngeal carcinoma (Wu et al. (2012) J. Gastroenterol. Hepatol. 27; 1312-1319), and melanoma (Rubinstein et al. (2004) Cancer Cell 5:241-251; Mathieu et al. (2012) J. Invest. Dermatol. 132:2245-2254). Gal1 expression has been identified as an adverse prognostic marker in the above-mentioned solid tumors. Moreover, Gal1 silencing is associated with anti-tumor effects in breast cancer (Croci et al (2012). J. Exp. Med. 209:1985-2000), prostate cancer (Dalotto-Moreno et al. (2013) Cancer Res. 73:1107-1117), lung cancer (Laderach et al. (2013) Cancer Res. 73:86-96), and melanoma (Rubinstein et al. (2004) Cancer Cell 5:241-251).
Given the broadly immunosuppressive activities of Gal1, these results suggest that Gal1 is a very powerful diagnostic marker that may potentially guide the targeted, rational therapy in many cancers. Although potent therapeutic (i.e., neutralizing) Gal1 monoclonal antibodies that protect Th1 and cytotoxic T cells from Gal1-induced apoptosis (Ouyang al, (2011) Blood 117:4315-4322); abrogate Gal1-associated tumor angiogenesis (Croci et al. (2012). J. Exp. Med. 209:1985-2000), and limit the growth of Gal1+ tumors in vivo (Croci et al. (2012) J. Exp. Med. 209:1985-2000) are known, such reagents may not be optimal for diagnostic and prognostic purposes.
In view of the above, it is clear that there remains a need in the art for compositions and methods to specifically detect Gal1, particularly in minimally invasive scenarios such as in serum-based assays.